SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

Discovery of novel heart rate-associated loci using the Exome Chip

van den Berg, ME; Warren, HR; Cabrera, CP; Verweij, N; Mifsud, B; Haessler, J; Bihlmeyer, NA; Fu, Y-P; Weiss, S; Lin, HJ; et al. van den Berg, ME; Warren, HR; Cabrera, CP; Verweij, N; Mifsud, B; Haessler, J; Bihlmeyer, NA; Fu, Y-P; Weiss, S; Lin, HJ; Grarup, N; Li-Gao, R; Pistis, G; Shah, N; Brody, JA; Müller-Nurasyid, M; Lin, H; Mei, H; Smith, AV; Lyytikäinen, L-P; Hall, LM; van Setten, J; Trompet, S; Prins, BP; Isaacs, A; Radmanesh, F; Marten, J; Entwistle, A; Kors, JA; Silva, CT; Alonso, A; Bis, JC; de Boer, R; de Haan, HG; de Mutsert, R; Dedoussis, G; Dominiczak, AF; Doney, ASF; Ellinor, PT; Eppinga, RN; Felix, SB; Guo, X; Hagemeijer, Y; Hansen, T; Harris, TB; Heckbert, SR; Huang, PL; Hwang, S-J; Kähönen, M; Kanters, JK; Kolcic, I; Launer, LJ; Li, M; Yao, J; Linneberg, A; Liu, S; Macfarlane, PW; Mangino, M; Morris, AD; Mulas, A; Murray, AD; Nelson, CP; Orrú, M; Padmanabhan, S; Peters, A; Porteous, DJ; Poulter, N; Psaty, BM; Qi, L; Raitakari, OT; Rivadeneira, F; Roselli, C; Rudan, I; Sattar, N; Sever, P; Sinner, MF; Soliman, EZ; Spector, TD; Stanton, AV; Stirrups, KE; Taylor, KD; Tobin, MD; Uitterlinden, A; Vaartjes, I; Hoes, AW; van der Meer, P; Völker, U; Waldenberger, M; Xie, Z; Zoledziewska, M; Tinker, A; Polasek, O; Rosand, J; Jamshidi, Y; van Duijn, CM; Zeggini, E; Jukema, JW; Asselbergs, FW; Samani, NJ; Lehtimäki, T; Gudnason, V; Wilson, J; Lubitz, SA; Kääb, S; Sotoodehnia, N; Caulfield, MJ; Palmer, CNA; Sanna, S; Mook-Kanamori, DO; Deloukas, P; Pedersen, O; Rotter, JI; Dörr, M; O'Donnell, CJ; Hayward, C; Arking, DE; Kooperberg, C; van der Harst, P; Eijgelsheim, M; Stricker, BH; Munroe, PB (2017) Discovery of novel heart rate-associated loci using the Exome Chip. Human Molecular Genetics, 26 (12). pp. 2346-2363. ISSN 0964-6906 https://doi.org/10.1093/hmg/ddx113
SGUL Authors: Jamshidi, Yalda

[img]
Preview
PDF Published Version
Available under License Creative Commons Attribution.

Download (513kB) | Preview

Abstract

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

Item Type: Article
Additional Information: © The Author 2017. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Genetics & Heredity, 06 Biological Sciences, 11 Medical And Health Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Human Molecular Genetics
ISSN: 0964-6906
Dates:
DateEvent
18 March 2017Accepted
3 April 2017Published Online
15 June 2017Published
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
MR/N025083/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
G0000934Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
068545/Z/02Wellcome Trusthttp://dx.doi.org/10.13039/100004440
G9521010DMedical Research Councilhttp://dx.doi.org/10.13039/501100000265
PG/02/128British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
083948Wellcome Trusthttp://dx.doi.org/10.13039/100004440
085475Wellcome Trusthttp://dx.doi.org/10.13039/100004440
108-1080315-0302Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
072960/Z/03/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
084726/Z/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
084727/Z/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
085475/Z/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
085475/B/08/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
BHF/RG/2000004British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
098051Wellcome Trusthttp://dx.doi.org/10.13039/100004440
PG/12/38/29615British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
URI: https://openaccess.sgul.ac.uk/id/eprint/108868
Publisher's version: https://doi.org/10.1093/hmg/ddx113

Actions (login required)

Edit Item Edit Item